Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This invention relates to treating fungal diseases. More particularly, this invention relates to the systemic treatment of fungal diseases by oral administration of an antifungal agent selected from tolciclate and tolnaftate and to medicaments containing said agents for oral administration.
• an antifungal agent selected from tolciclate and tolnaftate and to medicaments containing said agents for oral administration.
• the human body is subject to many fungal infections, some of which have been a problem to man since before recorded history. Modern science has been successful in treating many fungal diseases. The most success has occurred in the topical treatment on exposed areas of the body. Numerous compounds are known to be effective in such topical treatment. However, not all fungal infections occur in exposed areas and are thus not amenable to topical treatment. Some fungal diseases occur internally or deep in the dermal layer of the skin or in unexposed areas, such as under fingernails, and can only be treated systemically. Unfortunately, only a few antifungal agents are known to be systemically effective when administered orally. One of the most widely prescribed drugs for the systemic treatment of fungal diseases is griseofulvin. Since the chronic feeding of this drug to mice results in their developing liver tumors, its use is not justified in minor or trivial infections. Accordingly, there is great interest in finding antifungal agents which can be effectively and safely administered orally.
• Tolciclate and tolnaftate are known antifungal agents effective in topical treatment of fungal diseases.
• Tolciclate i.e., 0-(l,4-methano-l,2,3,4-tetrahydro-6-naphthyl)-N-methyl-N-(m-tolyl)-thiocarbamate having the formula is described in U.S. Patent No. 3,855,263.
• the patent indicates that the compound has antifungal activity when applied topically.
• Tolnaftate i.e., methyl-(3-methylphenyl)carba- mothioic acid O-2-naphthalenyl ester having the formula is described in U.S. Patent No. 3,334,126.
• this invention relates to (1) the method of treating fungal diseases which comprises orally administering to a person suffering therefrom a therapeutic amount of antifungal agent selected from tolciclate and tolnaftate and (2) an antifungal medicament for oral administration comprising: a. from about 10% to about 90% by weight of an antifungal agent selected from tolciclate and tolnaftate; and b. from about 90% to 10% by weight of a pharmaceutically acceptable carrier.
• the orally administered agents of this invention are relatively nontoxic.
• tolciclate when administered orally to rats, tolciclate was found to have an LD 50 of greater than 4000 mg/kg.
• LD 50 lethal dose to 50% of the animals being tested.
• Tolnaftate administered orally to rats was found to have an LD50 of greater than 5000 mg/kg.
• Typical fungus infections which can be treated systemically according to the process of this invention are ringworm infections of the skin, hair and nails, namely tinea corporis, tinea pedis, tinea cruris, tinea bar- bae, tinea capitis, tinea unguium and tinea versicolor when caused by organisms such as Microspora, Trichophyta, Epidermo- phyton floccosums, and Pityrospora, i.e., P. obiculare and P. ovale.
• Oral dosages in the order of 1 to 50 mg/kg, most preferably 5 to 25 mg/kg daily of the agents are highly effective in suppressing fungal diseases. Most preferably the agents will be administered in divided daily doses. The specific dosage will depend upon the site of the infection, type of fungus, and duration of treatment. Any pharmaceutical composition for oral administration containing the agents can be used in the process of this invention. In general, however, the agents will be administered in the form of tablets, capsules, syrups or suspensions.
• Typical dosage forms are as follows: A. The following ingredients are mixed in a blender for 5 minutes and then compressed into 200 mg. tablets:
• the gums are dispersed in about 1/2 the volume of water heated to 70°C. and then cooled to 35°C.
• the sucrose and D&C Red dye are dissolved in a small volume of the water and added to the gum dispersion.
• the tolciclate is dispersed in water and added to the gum dispersion.
• the parabens, vanillin and Alva Cherry flavoring are dissolved in alcohol and added to the dispersion.
• a quantity (7 grams) of adipic acid sufficient to adjust the pH to between 5 and 6 is added and finally the volume is adjusted to 10 liters with purified water.
• sustained release formulations and formulations containing other medicinal agents such as analgesics, antibiotics, etc.
• This example illustrates the absorption of tolciclate after oral administration and its migration to the skin.
• mice Fifteen male, Swiss-Webster mice weighing 25-30 g. were divided into groups of three. All animals were fasted overnight prior to the experiment. Food was allowed 8 hours after dosing.
• 14 C-tolciclate 0-(1,4-methano-1,2,3,4-tetrahydro-6-naphthyl)N-methyl-N-m-tolyl[methyl- 14 C]thiocarbamate, was prepared at a specific activity of 7.48 ⁇ Ci/mg. Powdered 14 C-tolciclate was suspended in 0.25% aqueous solution of methylcellulose at a concentration of 0.5 mg/ml. Each animal was gavaged with 10 mg/ml of suspension, resulting in a 5 mg/kg dose.
• Blood samples were taken at 0.5, 1, 2, 4, 8, 12, 48 and 72 hours after the dose of 14 C-tolciclate.
• 3 animals were killed and the liver, kidney, lung, skin, heart, spleen and brain tissues were removed. This procedure was repeated with 3 animals at 8, 24 and 72 hours.
• An estimation of biliary excretion was obtained by giving an intraperitoneal injection of 5 mg/kg of 14 C-tolciclate to 2 mice and following fecal elimination over a 72 hour period.
• Another group of 3 mice received a daily oral dose of 5 mg/kg of 14 C-tolciclate for 8 days. Blood was taken at 1, 5 and 8 days. The same tissues listed above were taken from this group on day 8.
• the major route of elimination was biliary, while about 25% of the dose was excreted via the urine.
• the drug was extensively metabolized, unchanged tolciclate was not found in the urine and only minute amounts were present in the blood.
• the major compound, identified by chromatography, in the skin was unmetabolized tolciclate. Based on the analysis, tolciclate levels in the skin ranged from 147-180 ng/g 4 hours after oral administration - this is a concentration that has been shown effective in in vitro antifungal testing.
• This example illustrates the effectiveness of tolciclate, tolnaftate and griseofulvin as antifungal agents when administered orally.
• mice Four groups of albino guinea pigs were observed for two weeks to make sure they were disease free. Following the observation period they were dosed according to the following regimen: one group (the control) was gavaged twice a day for 10 days with a 0.25% aqueous methylcellulose solution. The second group was gavaged twice a day for 10 days with 50 mg/kg of tolciclate suspended in a 0.25% aqueous solution of methylcellulose. The third group was gavaged twice a day for 10 days with 50 mg/kg of tolnaftate suspended in a 0.25% aqueous solution of methylcellulose. The fourth group was gavaged twice a day for 10 days with 50 mg/kg of griseofulvin in the form of a commercial elixir ("Grifulvin V" sold by Ortho Pharmaceutical Corp.).
• T. mentagrophytes "1782" fungus On the fifth day of treatment all of the animals were infected with T. mentagrophytes "1782" fungus by the following method: an area of several centimeters on the back of each guinea pig was shaved free of hair, abraded and inoculated with a suspension of a culture of T. mentagrophytes suspended in physiological saline solution. The resulting skin lesions were checked on day 7, 10 and 15 after inoculation and the size of the lesions measured.
• tolciclate was stopped 19 days after the first infection with T. mentagrophytes, 17 days later, (36 days after the first infection), all the guinea pigs were subjected to reinfection dermally with T. mentagrophytes. Those guinea pigs which had been treated with tolciclate did not become reinfected. The controls all became reinfected.
• Example 2 the data in this example may not look as impressive as the data in Example 2, Table 4, however, is has to be considered that in Example 2 the animals were treated with the medication first and then infected five days later. In Example 3 the animals are first infected and then treated with the medication five days later. It is quite unexpected to find that the treated animals retain their immunity to the fungus 17 days after the treatment was stopped. With most antifungal agents, the animal can be reinfected as soon as treatment with the agent is stopped.

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• Health & Medical Sciences (AREA)
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• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
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Citations (2)

• 1981
  • 1981-04-29 US US06/258,830 patent/US4348407A/en not_active Ceased
• 1982
  • 1982-04-19 EP EP82103281A patent/EP0063773A1/fr not_active Withdrawn
  • 1982-04-28 JP JP57070593A patent/JPS57183717A/ja active Pending
  • 1982-04-29 CA CA000401963A patent/CA1174169A/fr not_active Expired

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